Molecular Modelling and QSAR of Reversible Acetylcholines-terase Inhibitors

Kaur, Jaspreet; Zhang, M Q

doi:10.2174/0929867003375254

Cited by 72 publications

(54 citation statements)

References 25 publications

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“…Thus, although many inhibitor classes are known for AChE (53,54) and the 11␤HSDs (39) ␥-hydroxybutenolides and ␣,␤-unsaturated five-membered lactones were not described as AChE or 11␤HSD inhibitors until now.…”

Section: Discussionmentioning

confidence: 99%

Compound library development guided by protein structure similarity clustering and natural product structure

Koch

Wittenberg

Basu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

199

128

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To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11␤-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.combinatorial chemistry ͉ enzyme inhibition ͉ bioinformatics ͉ chemical biology ͉ ligand-sensing core

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Section: Discussionmentioning

confidence: 99%

Compound library development guided by protein structure similarity clustering and natural product structure

Koch

Wittenberg

Basu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

199

128

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“…In general, these inhibitors could be divided into 3 parts: the 5,6-dimethoxy-1-indanone moiety, the benzene ring moiety, and the protonated nitrogen moiety [30] . All the inhibitors formed major interactions with the active site of the enzyme through the 3 parts [31] . The 5,6-dimethoxy-1-indanone moiety of all the compounds was approximately located at the same site.…”

Section: Interactions Of Inhibitors With Achementioning

confidence: 99%

Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors

Shen

Liu

Tang

2007

Acta Pharmacologica Sinica

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Aim: To explore the binding mode of 2-substituted 1-indanone derivatives with acetylcholinesterase (AChE) and provide hints for the future design of new derivatives with higher potency and specificity. Methods: The GOLD-docking conformations of the compounds in the active site of the enzyme were used in subsequent studies. The highly reliable and predictive three-dimensional quantitative structure-activity relationship (3D-QSAR) models were achieved by comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. The predictive capabilities of the models were validated by an external test set. Moreover, the stabilities of the 3D-QSAR models were verified by the leave-4-out cross-validation method. Results: The CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient (q 2 ) and a non-cross-validated coefficient (r 2 ). The q 2 and r 2 obtained from the leave-1-out cross validation method were 0.784 and 0.974 in the CoMFA model and 0.736 and 0.947 in the CoMSIA model, respectively. The coefficient isocontour maps obtained from these models were compatible with the geometrical and physicochemical properties of AChE. Conclusion: The contour map demonstrated that the binding affinity could be enhanced when the small protonated nitrogen moiety was replaced by a more hydrophobic and bulky group with a highly partial positive charge. The present study provides a better understanding of the interaction between the inhibitors and AChE, which is helpful for the discovery of new compounds with more potency and selective activity.

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“…In such patients, treatment with cholinesterase inhibitors or immunosuppressants has been proposed [23,24] . The active triad of the AChE enzyme, on the other hand, is also the primary target of lethal organophosphorous (OP) compounds such as tabun, sarin, soman, and VX, which are known as nerve agents.…”

Section: Introductionmentioning

confidence: 99%

Differential binding of bispyridinium oxime drugs with acetylcholinesterase

et al. 2010

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Aim: To performe a time-dependent topographical delineation of protein-drug interactions to gain molecular insight into the supremacy of Ortho-7 over HI-6 in reactivating tabun-conjugated mouse acetylcholinesterase (mAChE). Methods: We conducted all-atom steered molecular dynamics simulations of the two protein-drug complexes. Through a host of protein-drug interaction parameters (rupture force profiles, hydrogen bonds, water bridges, hydrophobic interactions), geometrical, and orientation ordering of the drugs, we monitored the enzyme's response during the release of the drugs from its active-site. Results: The results show the preferential binding of the drugs with the enzyme. The pyridinium ring of HI-6 shows excellent complementary binding with the peripheral anionic site, whereas one of two identical pyridinium rings of Ortho-7 has excellent binding compatibility in the enzyme active-site where it can orchestrate the reactivation process. We found that the active pyridinium ring of HI-6 undergoes a complete turn along the active site axis, directed away from the active-site region during the course of the simulation. Conclusion: Due to excellent cooperative binding of Ortho-7, as rendered by several cation-π interactions with the active-site gorge of the enzyme, Ortho-7 may be a more efficient reactivator than HI-6. Our work supports the growing body of evidence that the efficacy of the drugs is due to the differential bindings of the oximes with AChE and can aid to the rational design of oxime drugs.

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Molecular Modelling and QSAR of Reversible Acetylcholines-terase Inhibitors

Cited by 72 publications

References 25 publications

Compound library development guided by protein structure similarity clustering and natural product structure

Compound library development guided by protein structure similarity clustering and natural product structure

Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors

Differential binding of bispyridinium oxime drugs with acetylcholinesterase

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